Most preventive agents are selected from a pool of successful cancer therapeutic drugs. The number of molecular pathway-specific compounds are few and the range of tumors that are sensitive relatively small. Clearly more drug development is needed, but the pace is slow and costs are high, contributing to high patient drug costs. One way to promote faster and more cost-effective drug development is through the identification of the molecular targets of presently known and effective drugs. One such drug is the estrogen modulator, tamoxifen. We propose to evaluate the precancerous mammary transcriptome, using global gene expression analysis, in mice that have received tamoxifen as a cancer preventive. These mice are genetically engineered to overexpress an oncogene in the mammary gland resulting in development of mammary tumors that mimic human breast tumors. In addition, similar to clinical breast cancer, when estrogen levels are inhibited in the precancerous period, tumorigenesis is significantly impaired. The overall goal of this proposal is to identify a gene expression signature predictive of tamoxifen sensitivity and thereby uncover genes that are targets of tamoxifen action. A long-term goal is to determine if the biomarker signature of tamoxifen sensitive gene expression in mice is valid for human breast. If true, these biomarkers can act as molecular targets for developing novel preventives and be used as surrogate endpoints in clinical trials. Aim: Interrogate the mammary transcriptome for estrogen-related targets during early carcinogenesis. Hypothesis: Tumorigenesis abrogation by estrogen reduction can be predicted by a specific signature of gene expression. SubAim A. Evaluate and compare the mammary transcriptomes of transgenic mice prone to mammary cancer after receiving a preventive regimen of tamoxifen or placebo. SubAim B. Characterize preinvasive lesions and tumors that are tamoxifen insensitve. The overall goal of this proposal is to identify molecules that mediate breast cancer prevention by tamoxifen in mice. If true, new drugs (or natural componds) that are more molecule-specific can be developed that have tamoxifen-like ability to interfere with breast cancer progression, but with lower toxicity. Knowing more about cancer molecules will bring more preventive agents quickly to clinical trials.